Iron overload, mitochondrial dysfunction and oxidative stress play pathogenic roles in the diabetes of hereditary hemochromatosis (HH) and may also be factors in common type 2 diabetes. The mouse model of HH (Hfe-/-) is characterized by decreased insulin secretion associated with oxidative stress and mitochondrial dysfunction in beta cells, although glucose tolerance is supranormal. Our studies of humans with HH reveal a similar phenotype: 31% had impaired glucose tolerance characterized by low insulin secretory capacity and increased insulin sensitivity. 22% of individuals with HH had diabetes, 89% of whom were overweight or obese suggesting that obesity-induced insulin resistance, independent of HH, could not be compensated because of the beta cell defect. Our Preliminary Data demonstrate: (A) Improved glucose tolerance in the Hfe-/- mice results from increased glucose uptake in muscle mediated by activation of AMP-dependent kinase (AMPK) and increased adiponectin, without a change in overall adiposity; (B) Decreased glucose and increased fatty acid oxidation are seen, with increased lactate production and hepatic glucose production from lactate, contributing to resistance to diet-induced obesity; (D) Mitochondria from Hfe-/- mice have increased oxidant stress resulting from a novel mechanism of iron interference with mitochondrial uptake of other metals, particularly Mn;(E) Near complete protection from obesity-associated diabetes in mice on a low iron diet;(F) Tissue iron stores are the best predictor of levels of the adipocyte hormone adiponectin in humans. All of these data are consistent with the hypothesis that iron levels, particularly as sensed by the adipocyte and skeletal muscle, lead to a phenotype protective from diabetes and obesity. At the same time, excess iron leads to beta cell damage and decreased insulin secretion. These data likely explain the association of increased iron intake with risk for type 2 diabetes and the metabolic syndrome. We propose experiments in mice to test hypotheses regarding the mechanisms for the regulation of fat and muscle metabolism by iron and the mechanisms for beta cell failure in the setting of high iron. These hypotheses will then be tested for applicability in understanding the human tissue-specific responses to iron overload. PUBLIC HEALTH RELEVANCE: High levels of iron are significantly associated with several forms of diabetes, including common type 2 diabetes and diabetes associated with the relatively common (1/200) hereditary disease hemochromatosis. In addition, iron is associated with cardiovascular disease, obesity, and lipid abnormalities that often accompany diabetes. We are studying the mechanisms for diabetes and other tissue abnormalities in humans with hereditary hemochromatosis and in a mouse model. Our data suggest that iron acts as a "poison" for mitochondria (the energy factories for cells) but also as a regulator of fat metabolism.